George H. Lambert

Community-Based Participatory Research: Lessons Learned from the Centers for Children's Environmental Health and Disease Prevention Research

Over the past several decades there has been growing evidence of the increase in incidence rates, morbidity, and mortality for a number of health problems experienced by children. The causation and aggravation of these problems are complex and multifactorial. The burden of these health problems and environmental exposures is borne disproportionately by children from low-income communities and communities of color. Researchers and funding institutions have called for increased attention to the complex issues that affect the health of children living in marginalized communities—and communities more broadly—and have suggested greater community involvement in processes that shape research and intervention approaches, for example, through community-based participatory research (CBPR) partnerships among academic, health services, public health, and community-based organizations. Centers for Children’s Environmental Health and Disease Prevention Research (Children’s Centers) funded by the National Institute of Environmental Health Sciences and U.S. Environmental Protection Agency were required to include a CBPR project. The purpose of this article is to provide a definition and set of CBPR principles, to describe the rationale for and major benefits of using this approach, to draw on the experiences of six of the Children’s Centers in using CBPR, and to provide lessons learned and recommendations for how to successfully establish and maintain CBPR partnerships aimed at enhancing our understanding and addressing the multiple determinants of children’s health.

Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer

Background Herbal mixtures are popular alternatives to demonstrated therapies. PC-SPES, a commercially available combination of eight herbs, is used as a nonestrogenic treatment for cancer of the prostate. Since other herbal medicines have estrogenic effects in vitro, we tested the estrogenic activity of PC-SPES in yeast and mice and in men with prostate cancer. Methods We measured the estrogenic activity of PC-SPES with transcriptional-activation assays in yeast and a biologic assay in mice. We assessed the clinical activity of PC-SPES in eight patients with hormone-sensitive prostate cancer by measuring serum prostate-specific antigen and testosterone concentrations during and after treatment. Results In complementary yeast assays, a 1:200 dilution of an ethanol extract of PC-SPES had estrogenic activity similar to that of 1 nM estradiol, and in ovariectomized CD-1 mice, the herbal mixture increased uterine weights substantially. In six of six men with prostate cancer, PC-SPES decreased serum testostero...

Semen quality after prenatal exposure to polychlorinated biphenyls and dibenzofurans

Large-scale poisoning occurred in central Taiwan in 1979 from ingestion of cooking oil contaminated by polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans. To determine whether in-utero exposure to these chemicals alters reproductive function, all prenatally exposed boys and appropriate controls were contacted for medical examination in 1998. Sperm of exposed children have increased abnormal morphology, reduced motility, and reduced capacity to penetrate hamster oocytes. Whether this will cause reduced fecundity, and how these effects can be extrapolated to the general population exposed to background levels of PCBs and dioxin-like chemicals, warrants further investigation.

Pilot Evaluation of Black Cohosh for the Treatment of Hot Flashes in Women

Background. Hot flashes cause significant morbidity in postmenopausal women, including women with breast cancer. We undertook a pilot study to estimate the effectiveness of black cohosh to reduce hot flashes. Methods. Women who reported significant hot flashes (≥ 14 per week) were enrolled. Black cohosh was given in the form of the commercial product Remifemin. The first week was a no-treatment baseline period, and therapy was given for the subsequent 4 weeks. Hot flash data were collected by daily questionnaires during baseline and treatment weeks. Adverse effects were recorded. Results. Twenty-one women completed the study. Their mean age was 56 years (range, 38–80). Thirteen patients had a history of breast cancer. Six patients were taking tamoxifen or raloxifene. Patients reported an average of 8.3 hot flashes per day during the baseline week. The reduction in mean daily hot flash frequency was 50% (95% CI, 34%–65%), while weekly hot flash scores were reduced 56% (95% CI, 40%–71%) at completion of the study. Overall, patients reported less trouble with sleeping, less fatigue, and less abnormal sweating. No patients stopped therapy because of adverse effects. Conclusions. Black cohosh appeared to reduce hot flashes and had a low toxicity. The efficacy found in this trial seems to be more than would be expected by a placebo effect (20%–30% hot flash reduction in previous trials). These results suggest that further evaluation of this black cohosh preparation with a phase III randomized trial is indicated.

Risk of Autistic Disorder in Affected Offspring of Mothers With a Glutathione S-Transferase P1 Haplotype

OBJECTIVES To delineate the natural history of pityriasis rosea in black children and to compare our findings with those of the American, European, and African literature on pityriasis rosea. Textbook and journal article descriptions of pityriasis rosea usually offer information about the presentation and clinical course of this condition in white patients. DESIGN Prospective observational study. SETTING The general pediatric clinic, adolescent clinic, and emergency department of Childrens Hospital of Michigan, Detroit, from June 2003 through May 2005. PATIENTS We followed up 50 black children with pityriasis rosea from the time of diagnosis through follow-up visits at 1, 2, and 4 weeks. Detailed observations were made and digital photographs taken at each visit. MAIN OUTCOME MEASURES Duration of illness and pigmentary sequelae. RESULTS Similarities with the medical literature were found regarding season of onset and prevalence of pruritus and of a herald patch. Our patients had more frequent facial involvement (30%) and more scalp lesions (8%) than usually described in white populations. One third had papular lesions. The disease resolved in nearly one half of patients within 2 weeks. Residual hyperpigmentation was seen in 48% of patients. Hypopigmentation developed in 29% of patients with purely papular or papulovesicular lesions. CONCLUSIONS Pityriasis rosea in black children differs in several ways from textbook descriptions. Physicians may use this information to better counsel patients about the course and potential sequelae of this condition.

The effect of age, gender, and sexual maturation on the caffeine breath test.

This study demonstrated the feasibility of utilizing the (3-13C-methyl) caffeine breath test (CBT) in children and adolescents, and examined the effect of gender, age, and puberty on the CBT. The CBT, expressed as the 2-hour accumulative exhalation of labeled CO2 (2-hour CO2), was compared to the CBT results in the adult. The 2-hour CO2 values were higher in the children than the adult, and the decrease in the CO2 values occurred in males during late puberty and in females during early puberty.

Analysis of case-parent trios at a locus with a deletion allele: association of GSTM1 with autism

BackgroundCertain loci on the human genome, such as glutathione S-transferase M1 (GSTM1), do not permit heterozygotes to be reliably determined by commonly used methods. Association of such a locus with a disease is therefore generally tested with a case-control design. When subjects have already been ascertained in a case-parent design however, the question arises as to whether the data can still be used to test disease association at such a locus.ResultsA likelihood ratio test was constructed that can be used with a case-parents design but has somewhat less power than a Pearsons chi-squared test that uses a case-control design. The test is illustrated on a novel dataset showing a genotype relative risk near 2 for the homozygous GSTM1 deletion genotype and autism.ConclusionAlthough the case-control design will remain the mainstay for a locus with a deletion, the likelihood ratio test will be useful for such a locus analyzed as part of a larger case-parent study design. The likelihood ratio test has the advantage that it can incorporate complete and incomplete case-parent trios as well as independent cases and controls. Both analyses support (p = 0.046 for the proposed test, p = 0.028 for the case-control analysis) an association of the homozygous GSTM1 deletion genotype with autism.

Genetic variant of glutathione peroxidase 1 in autism

Genetic factors can contribute to autistic disorder (AD). Abnormal genes of oxidative stress pathways and increased oxidative stress have been reported in autism spectrum disorders. Polymorphisms of genes involved in glutathione metabolism, e.g. GSTP1 and GSTM1 are reportedly associated with autistic disorder. We investigated a GCG repeat polymorphism of a human glutathione peroxidase (GPX1) polyalanine repeat (ALA5, ALA6 and ALA7) in 103 trios of AD (probands and parents) using the transmission disequilibrium test. Significant transmission disequilibrium (p=0.044) was found in the overall transmission of the three alleles. The ALA6 allele was under transmitted (p=0.017). These results suggest that possessing this ALA6 allele may be protective for AD. Future study of interaction of the GPX1 GCG repeat and other gene polymorphisms such as the MnSOD ALA16 or the GPX1 Pro198Leu polymorphism in this cohort of AD families may shed light in whether the combination of the ALA6 allele with another polymorphism of antioxidant allele contributes to the increased oxidative stress in autism.

HLA-DR4 as a Risk Allele for Autism Acting in Mothers of Probands Possibly During Pregnancy

OBJECTIVES To test whether HLA-DR4 acts in the mother, possibly during pregnancy, to contribute to the phenotype of autistic disorder in her fetus. DESIGN Transmission disequilibrium testing in case mothers and maternal grandparents. SETTING Previous studies have consistently shown increased frequency of HLA-DR4 in probands with autism and their mothers, but not their fathers. However, this has been documented only in case-control studies and not by a more direct study design to determine whether HLA-DR4 acts in mothers during pregnancy to contribute to autism in their affected offspring. PARTICIPANTS We genotyped for HLA-DR alleles in members of 31 families with parents and maternal grandparents. Probands with autism were tested using the Autism Diagnostic Observation Schedule-Western Psychological Services and Autism Diagnostic Interview, Revised. There was 80% power to detect an odds ratio of 3.6. Participants were all families from New Jersey and were similar in number to earlier studies of autism and HLA-DR4. OUTCOME MEASURES Analysis was by standard transmission disequilibrium testing. As a secondary test we examined the possibility of maternal imprinting. RESULTS Significant transmission disequilibrium for HLA-DR4 was seen (odds ratio, 4.67; 95% confidence interval, 1.34-16.24; P = .008) for transmissions from maternal grandparents to mothers of probands, supporting a role for HLA-DR4 as an autism risk factor acting in mothers during pregnancy. Transmission disequilibrium was not seen for HLA-DR4 transmissions from parents to probands or from mothers to probands. CONCLUSIONS The HLA-DR4 gene may act in mothers of children with autism during pregnancy to contribute to autism in their offspring. Further studies are required to confirm these findings.

Biomarker Measurements in a Coastal Fish-Eating Population Environmentally Exposed to Organochlorines

The Lower North Shore region of the St. Lawrence River is home to a fish-eating population that displays an unusually high body burden of several organochlorines, including polychlorinated biphenyls (PCBs) and dioxin-like compounds (DLCs). We measured biomarkers indicative of liver enzyme induction and investigated the relationship with organochlorine body burden in adult volunteers from this population. We determined plasma concentrations of PCBs and chlorinated pesticides by high-resolution gas chromatography (HRGC) with electron capture detection. DLC concentrations were measured by the dioxin-receptor chemically activated luciferase expression (DR-CALUX) assay and in a subset of participants, by HRGC/high-resolution mass spectrometry. We measured cotinine, d-glucaric acid, and porphyrins in morning urine samples and determined liver CYP1A2 activity in vivo using the caffeine breath test. Neither DLC concentrations as measured by the DR-CALUX nor PCB-153 concentrations, the latter representing total PCB exposure, were correlated with biomarkers of effects. Smoking (morning urinary cotinine concentration) was positively related to CYP1A2 activity as measured by the caffeine breath test (p < 0.01). Liver CYP1A2 activity was in turn negatively correlated with PCB-105:PCB-153 and PCB-118:PCB-153 congener ratios (p < 0.05). Hence, despite the relatively high body burden of PCBs and DLCs in this population, only smoking had a significant correlation with biomarkers of hepatic enzyme induction. Our data are consistent with smoking-induced liver CYP1A2 activity altering heme metabolism and increasing the biotransformation of mono-ortho PCB congeners.